Dispersions for the formulation of slightly or poorly soluble agents

ABSTRACT

The invention provides a dispersion having an oily phase, an aqueous phase, in the form of an oil-in-water emulsion or a water-in-oil emulsion, and at least one active ingredient that is only slightly or with difficulty soluble in the oily phase and the aqueous phase. The dispersion is free from toxicologically dangerous organic solvents. The dispersion contains the active ingredient dissolved in a quantity that is greater than the quantity which results additively from its maximum solubility in the oily and the aqueous phase of the emulsion prior to forming the emulsion.

This application is a continuation of U.S. application Ser. No.09/915,549, filed Jul. 27, 2001, which claims priority to German PatentApplication No. 10 36 871.9, filed on Jul. 28, 2000, the completedisclosure of which is incorporated herein by reference.

1. FIELD OF THE INVENTION

The invention relates to dispersions having an oily phase, an aqueousphase, and an active ingredient, which the active ingredient can only bedissolved slightly or is insoluble in both phases.

2. BACKGROUND OF THE INVENTION

Active ingredients with low solubility very often have the problem ofinsufficient bioavailabiliy. The solution generally adopted for thisproblem is increasing the solubility of these active ingredients.Examples of this are using a dissolving intermediary via solubilization,the formation of inclusion compounds (e.g. with cyclodextrines) and theuse of solvent mixtures (K. H. Bauer, K.-H. Frömming, C. Führer,Pharmazeutische Technologie, Georg Thieme Verlag Stuttgart, 1991). Formany active ingredients, however, this does not lead to a sufficientincrease in solubility, especially if active ingredients aresimultaneously difficult to dissolve in aqueous media and in organicmedia. Here, for example, solvent mixtures are ruled out as a solutionto the problem. Alternatively active ingredients which are only slightlysoluble in water can be dissolved in oils, an O/W emulsion can beproduced and this can then be administered orally or parenterally,usually intravenously. Very many active ingredients, especially activeingredients which are at the same time only slightly soluble in aqueousand organic media, are however not sufficiently soluble in oils. Notsufficiently means that, because the solubility is too low, the volumeof emulsion to be administered for the necessary dose is too large.

Active ingredients that are only slightly soluble in water and in oils,such as Amphotericin B, can however be incorporated into emulsions (Sekiet al. U.S. Pat. No. 5,534,502). To achieve this, however, additionalorganic solvents must be used. These solvents must then be removed againin intermediate stages of the emulsion production or from the product(Davis, Wash., EP 0 296 845 A1) in which however a certain residualsolvent content remains in the product. In addition, this productionprocess takes a great deal of time, and is cost-intensive, so thatpractically no products based on this technology are represented on themarket. An alternative method is the intercalation of such substances asAmphotericin B into the phospholipid double membrane of liposomes; acommercial product is for example AmBisome® (Janknegt et al., Liposomaland lipid formulations of amphotericin B., Clin. Pharmacokinet.,23,279-291 [1992]). A disadvantage of this, however, is the veryexpensive production process, which means that, as a rule, it is usedonly in emergencies, when another treatment does not achieve the aim, oronly for patients who are financially in a position to pay for thetreatment. Thus there is a clear need for an economical formulation,which is at the same time as simple as possible to produce, unlikeliposomes is stable in storage, does not require lyophilization and doesnot contain residual solvents.

There is therefore need for a dispersion which contains an activeingredient, which hitherto could only be dissolved slightly, withdifficulty or not at all, that is dissolved in a quantity hitherto notpossible. There is also a need for a dispersion which avoids thedisadvantages described above, such as the use of additional organicsolvents hitherto necessary to form a formulation.

SUMMARY OF THE INVENTION

An object of the present invention is to form a dispersion based on anoil-in-water (“O/W”) emulsion or a water-in-oil (“W/O”) emulsion loadedwith active ingredient, which can at the same time be dissolved in waterand in oils only slightly, or with difficulty, or not at all.

Another objective of the invention is to form a dispersion which is freeof toxicologically dangerous organic solvents and containing the activeingredient dissolved in a quantity that is higher than the quantityresulting additively from its maximum solubility in the water and theoil phase of the emulsion.

These objectives and other objectives are obtained by a dispersion whichcomprises:

an oily phase;

an aqueous phase, in the form of an oil-in-water emulsion or awater-in-oil emulsion; and

at least one active ingredient that is only slightly or with difficultysoluble in the oily phase and the aqueous phase, wherein the dispersionis free from toxicologically dangerous organic solvents and contains theactive ingredient dissolved in a quantity that is greater than thequantity which results additively from its maximum solubility in theoily and the aqueous phase of the emulsion.

The invention also provides a method for the production of a dispersionwhich comprises:

an oily phase;

an aqueous phase, in the form of an oil-in-water emulsion or awater-in-oil emulsion; and

at least one active ingredient that is only slightly or with difficultysoluble in the oily phase and the aqueous phase, wherein the dispersionis free from toxicologically dangerous organic solvents and contains theactive ingredient dissolved in a quantity that is greater than thequantity which results additively from its maximum solubility in theoily and the aqueous phase of the emulsion, wherein the methodcomprises;

combining the aqueous phase, oily phase, and active ingredient to form apre-dispersion in which the active ingredient is not completelydissolved; and

mixing the emulsion to form the dispersion.

Preferably, the quantity of active ingredient dissolved is greater thanthe additive quantity by a factor of 2, more preferably 5, still morepreferably 10 or even greater. The “additive quantity” is determined bydissolving the maximum possible quantity of active ingredient in theseparate oily and aqueous phases (dissolving conditions being otherwiseidentical) corresponding to the constituents in the dispersion(saturation concentration), no further additional organic solvents beingused. The dispersion according to the invention contains, in addition tothe additive quantity, a superadditive quantity of dissolved activeingredient.

An important characteristic according to the invention is that, with thesame composition, high-energy homogenization is preferably carried out,compared with low-energy dispersion (shaking, or blade stirrer).

The production of the dispersion according to the invention is carriedout in particular excluding toxicologically dangerous organic solventssuch as e.g. methylene chloride and ethanol. The active ingredients areincorporated directly from the solid substance into the emulsion,avoiding an intermediate step.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B:

Particle size distribution of the Amphotericin powder beforeincorporation into the dispersion (1A) and particle size analysis of thedispersion according to the invention following incorporation of theAmphotericin powder (1B, Example 1), the drug particles are no longerdetectable (laser diffractometry).

FIG. 2:

Light microscopic photograph of the Amphotericin powder beforeincorporation into the O/W emulsion (Example 1) (Polarization photographin dark field, anisotropic crystals appear white, bar as in FIG. 3 (10μm).

FIG. 3:

Light-microscopic photograph of the O/W emulsion after incorporation ofthe Amphotericin powder from FIG. 2 (Example 1) (polarizationphotograph, in dark field only diagrammatic reflexes of the isotropicemulsion drops, bar 10 μm).

FIG. 4:

Light microscopy graph of undiluted emulsion from example 18.

FIG. 5:

Light microscopy graph of emulsion with 1 mg/mL Amphotericin B fromexample 19.

FIG. 6:

Light microscopy graph of dispersion containing 5 mg/mL Amphotericin Bfrom example 19.

DETAILED DESCRIPTION OF THE INVENTION

It is a generally recognized state of the art, that the molecules of anactive ingredient that can be dissolved only with difficulty orslightly, must be incorporated from the solid aggregate condition(powder) via at least one intermediate step (e.g. molecular dispersivedistribution in a solvent) into an emulsion as a carrier system.Experience shows that in the case of substances that are only veryslightly soluble in water and oil at the same time, it is not sufficientto add crystals of the active ingredient to the emulsion. Thus theadmixture of Amphotericin B-solution (solvent mixture), sometimes madeto a commercial O/W emulsion such as Intralipid or Lipofundin, leads tothe precipitation of the active ingredient, Amphotericin B crystals areproduced, which sediment and do not dissolve in the emulsion.

Surprisingly, it has now been found that the production of an emulsionsystem with dissolved active ingredient is also possible direct from thesolid aggregate condition of the active ingredient. To produce thedispersion according to the invention, the active ingredient is added tothe aqueous phase or the oil phase in particle form and then allcomponents are subjected to a fairly high- or high-energy process suchas, for example, homogenization, especially high pressurehomogenization. The high-energy process of high pressure homogenizationleads to incorporation of the active ingredient into the emulsion bymolecular dispersion, and no active ingredient crystals remaindetectable in the polarization microscope. The emulsions obtainedsurprisingly have a stability similar to that of systems produced usingorganic solvents.

A very simple way of incorporating the active ingredient crystals istrituration of the active ingredient with a commercial O/W emulsion(e.g. Lipofundin, Intralipid). After trituration, the active ingredientis found primarily in the water phase, a disperse system has beenproduced, which, as an internal phase, simultaneously contains drops ofoil and active ingredient crystals. This disperse system is thensubjected to homogenization or high pressure homogenization (e.g. 1,500bar and 5-20 homogenization cycles). A finely dispersed emulsion isobtained (Example 1) in which, at the end of the homogenization processno active ingredient crystals remain detectable. The crystals havealmost completely or completely dissolved, i.e. using a lightmicroscope, even with 1000-fold magnification, in 2 out of 3 fields, nomore than 10 crystals, preferably no more than 5 crystals and especiallyno more than 1 crystal can be detected.

If desired, the active ingredient can, however, also be used in aquantity such that, at the end of the homogenization process, inaddition to the dissolved part of the active ingredient, a part of theactive ingredient in undissolved crystalline form is still present,which forms a depot.

Alternatively an aqueous suspension of the active ingredient can bemixed with an O/W emulsion. Again it is a disperse system with adispersed phase of drops of oil and crystals of active ingredient. Thisis likewise subjected to a fairly high-, or high-energy process such ashigh pressure homogenization. Admixture of the active ingredient as anaqueous suspension is especially suitable if the active ingredientconcentration is relatively low. In addition the aqueous suspension ofthe active ingredient can be subjected to a grinding process describedin the textbooks before the admixture, e.g. wet grinding with a colloidmill, a pearl mill or a bead mill, or pre-pulverized by high pressurehomogenization.

In general it is favorable to use the active ingredients in the form ofvery fine crystals, i.e. in micronized form with a particle size rangingfrom ca. 0.1 μm to 25 μm (colloid mill, gas-jet mill).

Alternatively the active ingredient can also be dispersed in the oil.The oil with the active ingredient crystals is then dispersed in thewater phase, during which the necessary surfactant is either added tothe water phase or dissolved in the oil phase or dispersed in each case.In the case of lecithin, the lecithin can be dispersed in the water ordissolved in the oil phase whilst being slightly heated.

In the case of incorporation of the active ingredient crystals into theoil phase, this can take place without the addition of a surfactant. Thesurfactant, e.g. lecithin, is then added. Alternatively the activeingredient crystals can also be incorporated into an oil phase, whichalready contains surfactant.

After incorporation of the active ingredient crystals into the oil, theoil phase is dispersed in water (e.g. with a high-speed agitator) andthe raw emulsion obtained is then subjected to high pressurehomogenization. Here too it is favorable to use the active ingredientcrystals as small as possible. For the further comminution of the activeingredient crystals incorporated into the oil phase, this oilysuspension, before producing the raw emulsion, can first be subjected togrinding. The active ingredient crystals in the oil phase are furthercomminuted by this wet grinding, partially into the nanometer range.Usual wet grinding processes which can be used are, for example, thecolloid mill and high pressure homogenization of the oil phase. Ingeneral the cavitation of an aqueous phase is the recognized principleof comminution in the case of high pressure homogenization, i.e thepresence of water is necessary for the cavitation. Oils with anextremely low vapor pressure compared to water cannot be used forcavitation. In spite of this it was surprisingly found that sufficientcomminution occurs for the production of the new carrier system.

It is characteristic of the dispersion according to the invention, thatthe active ingredient incorporated in the emulsion is present dissolvedin a higher quantity than that resulting additively from its maximumsolubility in the water and oil phase of the emulsion, and at the sametime no toxicologically dangerous organic solvents were used forproduction. Such toxicologically dangerous organic solvents include inparticular chloroform, methylene chloride, fairly long-chained alcoholssuch as hexanol and octanol, but also ethanol in fairly highconcentrations.

As a rule, the active ingredients according to the invention are activeingredients that are only slightly soluble (1 part dissolves in 30-100parts solvent) or difficult to dissolve (1 part dissolves in 100-1000parts solvent), but especially very difficult to dissolve (1 partdissolves in 1,000 to 10,000 parts solvent) or even insoluble (>10,000parts solvent).

Thus the solubility of Amphotericin B in water is less than 0.001%(<0.01 mg/ml) at pH 6-7, i.e. the pH value of the emulsion. It is truethat the solubility of Amphotericin is higher with pH 2 and pH 11 (0.1mg/ml), however these solutions cannot be administered intravenously.

The solubility of Amphotericin in soya oil (Long-chainTriglycerides—LCT) and in Miglyol 812 (Medium-chain Triglycerides—MCT),the standard oils for most commercially available emulsions forparenteral infusion is less than 0.0001 mg/ml.

40 g emulsion from Example 1 consist 20% of oil (8 g) and ca. 80% ofwater (32 g). Thus on the basis of these solubilities, 8×0.0001 mg/mlplus 32×0.01 mg/ml, i.e. in total 0.3208 mg Amphotericin can bedissolved in 40 g emulsion components oil and water (i.e. approx. 0.008mg/ml emulsion). In the present emulsion according to the invention 0.2mg/ml emulsion could be incorporated (Example 1) without microscopiccrystals of undissolved drug being detectable (Example 12). A higherconcentration than 1 mg/ml emulsion could also be incorporated (Example2), with laser diffractometry none of the drug particles used forproduction remained detectable (Example 11).

In the case of a desired dose of e.g. 100 mg Amphotericin B, thedispersions according to the invention with 1 or 0.2 mg/ml emulsion,result in a volume of 100 to 500 ml emulsion to be administeredintravenously. Thus with the emulsion according to the invention, activeingredients which dissolve only slightly, or are difficult to dissolve,can for the first time be administered in a sufficiently smalladministration volume with well-tolerated pH values.

Dissolved active ingredient is rapidly available. For production of adepot preparation, more active ingredient can be incorporated into thedispersion than will dissolve in it, i.e. crystals are produced whichact as a depot. The solubility in water and oil phase amounts to, forexample, 0.008 mg/ml in the case of Amphotericin B, the emulsionaccording to the invention dissolves without detectable crystals e.g.0.2 mg/ml (Example 1). If 5 mg/ml dispersion is incorporated, thesolubility is exceeded (supersaturated system). Following high pressurehomogenization, in addition to the dissolved active ingredient, veryfine drug crystals are obtained (Example 15).

The heterogeneous, supersaturated dispersions produced by mixture of adrug (Example 15) or drug suspension (analogous to Example 6) with anemulsion are characterized in that small drops of oil and very finecrystals exist separately side by side, i.e. the crystals are primarilyoutside the oil drops.

Determination of the particle size is carried out by light microscopy,whilst establishing the number distribution. Alternatively this can bedetermined by laser diffractometry (Equipment: Coulter LS 230, CoulterElectronics, Krefeld, Germany), the volume distribution obtained can beconverted into the number distribution.

If, in the dispersion with a high load of active ingredient, furtherdrug crystals are present beside the emulsion droplets, directly afterproduction at least 90%, and preferably 95% of the number of activeingredient crystals in the number distribution are smaller than 5 μm.With the application of high pressures (e.g. 1000 bar) and a sufficientnumber of homogenization cycles, highly disperse systems are obtained.Depending on pressure and number of cycles, dispersions are obtainedwith at least 90%, in some cases 95% and especially 99% of the number ofcrystals in the number distribution smaller than 1 μm.

A description is given above, of the in situ production of the activeingredient depot from small crystals, by production of the dispersionaccording to the invention with an active ingredient quantity above thesaturation solubility of the system. Alternatively a dispersionaccording to the invention can also be produced with exclusivelydissolved active ingredient, to which active ingredients of definitesize are subsequently admixed, e.g micronized active ingredient.

To produce the dispersion according to the invention, commercial O/Wemulsions can be used (e.g. Lipofundin, Intralipid, Lipovenoes,Abbolipid, Deltalipid and Salvilipid), or an emulsion is produced fromoil phase, emulsifier/stabilizer and outer phase (e.g. water).

Examples of constituents of the oil phase of the emulsions are: soyaoil, safflower oil (thistle oil), long-chain triglycerides (LCT),medium-chain triglycerides (MCT) such as, for example, miglyols, fishoils and oils with an increased constituent of unsaturated fatty acids,acetylated partial glycerides such as in Stesolid, individually or inmixtures.

For stabilization of the dispersions, emulsifiers and stabilizers can beused. These are possibly already contained in the emulsion used toproduce the dispersion according to the invention, addition of furtheremulsifiers and stabilizers can be advantageous in the production of thedispersion.

Examples of emulsifiers are e.g. egg-lecithin, soya lecithin,phospholipids of egg or soya, Tween 80, sodium glycocholate and sodiumlauryl sulphate (SDS). Alternatively stabilization can be carried out bythe addition of substances which have the effect of increasing stabilityby mechanisms other than emulsifiers, e.g. by steric stabilization orincrease of the zeta potential. Such stabilizers are e.g. blockco-polymers such as e.g. poloxamers (e.g. Poloxamer 188 and 407) andpoloxamines (e.g. Poloxamine 908), polyvinyl pyrrolidon (PVP), polyvinylalcohol (PVA), gelatine, polysaccharides such as hyaluronic acid andchitosan and their derivatives, polyacrylic acid and its derivatives,polycarbophil, cellulose derivatives (e.g. methyl-, hydroxypropyl- andcarboxymethyl cellulose), sugar esters such as saccharose monostearateand antiflocculants such as sodium citrate. Emulsifiers and stabilizerscan be used individually or in mixtures. Typical concentrations are 0.1%to 20%, especially 0.5% to 10%. All amounts used herein are wt. %, basedon the total weight of the dispersion, unless otherwise stated.

As an aqueous outer phase of the O/W emulsion used for production of thedispersion according to the invention the following can be used: water,mixtures of water with other water-miscible organic liquids, liquidpolyethylene glycols (PEG, especially PEG 400 and 600).

The aqueous outer phase can also contain additives, e.g. electrolytes,non-electrolytes (e.g. glycerol, glucose, mannitol, xylite, forisotonization), gel forming agents such as cellulose derivatives andpolysaccharides such as xanthane and alginate (e.g. to increaseviscosity).

For topical application, penetration enhancers (e.g. azone, lauric acid)can be added to the dispersion and for application to thegastrointestinal tract, absorption enhancers (e.g. bile acids,lysophospholipids) can be added.

Active ingredients for incorporation into the emulsion are, besidesAmphotericin B, e.g. Ciclosporin, Buparvaquone and Atovaquone. Furtheractive ingredients are hormones (e.g. estradiol), antioestrogens andcorticoids (e.g. Prednicarbate).

Administration of the emulsion can be carried out using differentroutes, e.g. parenterally, but also orally or topically. In the case ofparenteral administration, all the usual methods are possible, e.g.intra- and subcutaneous, intramuscular, intra-articular, intraperitonealetc.

Topical emulsions with Cyclosporin can improve the penetration of theactive ingredient into the skin because of the high constituent of thedrug dissolved (increased concentration gradient). Oral administrationof the Cyclosporin emulsion can increase the bioavailability as, incontrast to micronized Cyclosporin, an increased dissolved constituentis present.

The bioavailability of orally administrated Amphotericin B is almostzero due to its low solubility. Oral administration of the Amphotericinemulsion can also increase the bioavailability due to the increaseddissolved constituent.

The emulsions according to the invention (e.g. with Buparvaquone andAtovaquone) can, following intravenous injection, also be used fortissue-specific drug administration, by combination with a targetingunit (e.g. Apolipoprotein E in combination with Apolipoprotein AI andAIV) (targeting to the brain). In certain diseases of themonocyte/phagocyte system (MPS) exciters also become localized in thebrain and hitherto have been difficult to access for therapy (e.g.Leishmanioses, Toxoplasmosis).

The systems described above are of O/W type, that means oil droplets aredispersed in the water phase. It is also possible to produce W/Oemulsion based dispersions. A basic advantage is that the outer oilphase acts as a diffusion barrier prolonging drug release. Suchdispersions cannot be administered intravenously, but they can e.g. beinjected intramuscularly or subcutaneously as depot formulation.Application of W/O systems to the eye increases the retention time inthe eye due to the increased viscosity and simultaneously providesprolonged drug release. For topical application to the skin, the oilphase has an occlusive effect increasing drug penetration. From this,the W/O type systems have advantages for special applications. Preferredform of the invention is however the O/W type dispersion.

For oil-in-water emulsions the dispersion is characterized in that itcontains 5 to 99.5% by weight of aqueous phase, preferably 10 to 95% byweight of aqueous phase, more preferred 60 to 95% by weight andspecifically 70 to 95% by weight of aqueous phase, based on the weightof the total dispersion.

For water-in-oil emulsions the dispersion is characterized in that itcontains 5 to 30% by weight of aqueous phase, preferably 10 to 25% byweight of aqueous phase, more preferred 10 to 20% by weight of aqueousphase, based on the weight of the total dispersion.

The ingredients of the oil phase of the emulsions are—as mentionedabove—in particular selected from the group consisting of soya oil,safflower oil, long-chain triglycerides (LCT), medium-chaintriglycerides (MCT), such as miglyols, fish oils and oils with anincreased amount of constituent of unsaturated fatty acids, acetylatedpartial glycerides, such as in Stesolid®, individually or in mixtures.The medium-chain triglycerides contain preferably at least 90%triglycerides of caprylic acid (C8) and of capric acid (C10). Accordingto the invention mixtures of soya oil and MCT are suitable as oil phase,in particular in a weight ratio of 5:1 to 1:5, preferably 2:1 to 1:2 or1:1.

The oil phase of the invented dispersions can consist of oils, thatmeans lipids being liquid at room temperature of 20° C. It is alsopossible to blend these oils with lipids being solid at room temperatureof 20° C. The blending mixture of oil and solid lipid can range from99+1 to 1+99. Preferred blending mixtures contain a minimum of 10 partsliquid oil, especially 30 parts liquid oil and most favorable at least50 parts liquid oil.

In special cases the lipid phase of the dispersion can consist 100% oflipid being solid at room temperature of 20° C. In case of lipidsmelting close to room temperature, this leads to dispersions of lipiddroplets being in a super-cooled melt state. In case of very highmelting lipids—despite the melting point depression according to theThomson equation—the particles of the dispersion can harden. The Thomsonequation describes that the melting point of lipids is stronglydepressed compared to the bulk ware in case they crystalline as veryfine particles (i.e. nanoparticles or having a size of a few micrometer)(Hunter, R. J., Foundations of colloid science, Vol. 1, OxfordUniversity Press, Oxford, 1986).

Examples for lipids being solid at room temperature are carnauba wax,hydroxyoctacosanyl hydroxystearate, Chinese wax, cetyl palmitate,beeswax and similar waxes. Further examples of these solid substancesinclude C₂₀₋₄₀ di- and triglycerides, including those which containunsaturated fatty acids, C₂₀₋₄₀ fatty alcohols, C₂₀₋₄₀ fatty amines andtheir compounds, sterols.

Suitable lipids for the production of blends from liquid and solidlipids are: Natural and synthetic triglycerides and mixtures thereof,monoglycerides and diglycerides, alone or mixtures thereof or mixtureswith e.g. triglycerides, self-emulsifying modified lipids, natural andsynthetic waxes, fatty alcohols including their esters and ethers andmixtures thereof. Especially suited are synthetic monoglycerides,diglycerides and triglycerides as individual substances or mixturesthereof (e.g. hard fat), Imwitor 900, triglycerides (e.g.glyceroltrilaurate, glyceroltrimyristate, glyceroltripalmitate,glyceroltristearate and glyceroltribehenate) and waxes as e.g.cetylpalmitate, carnauba wax and white wax (German pharmacopeia). Inaddition paraffins, e.g. solid paraffin.

The droplet size of the oil droplets (O/W type) or water droplets (W/Otype) in the dispersion is above 100 nm (determined by photoncorrelation spectroscopy—PCS). The recommended upper size limit is 10μm, otherwise creaming will occur due to flotation of the dropletsleading to physical instability (droplet coalescence). To minimizeflotation, the size should be below 5 μm, preferentially below 1 μm (PCSdiameter) leading to so-called physically “autostable” dispersions.Optimum physical stability was found in the size range similar toparenteral fat emulsions with PCS diameters of 200 nm to 500 nm.

The stabilizer content in parenteral preparations should be kept as lowas possible to minimize toxicity and distortions of metabolism. Fromlecithin-containing emulsions for parenteral nutrition it is known, thata too high administration of lecithin can cause metabolic distortions,typical daily volumes administered are e.g. 500 ml emulsion and more.This lead to the development of lecithin-reduced emulsions, that meansgoing even further down from 1.2% lecithin to 0.6% lecithin. Somesystems for the delivery of poorly soluble drugs use a relatively highemulsifier content (e.g. solubilization with su rfactants, SEDDS—self-emulsifying drug delivery systems based on the solubilizationof oil by high surfactant concentrations). A special feature of thepresent invention is that it minimizes the surfactant load.

A typical composition of OIW type of the invented dispersions is: 20 goil, 1.2 g lecithin, 0.1 g drug and 78.3 g water. That means the 21.2 gproduced oil droplets consisted of 20 g oil phase (=94.3%) and 1.2 gstabilizer (=5.7%).

Further examples of emulsifiers are in addition to lecithines thepolyethoxysorbitanesters (Tween®-types), such as e.g. laurate (Tween20/21), palmitate (Tween 40), stearate (Tween 60/61), tristearate (Tween65), oleate (Tween 80/81), or trioleate (Tween 85) esters, sodiumglycocholate and sodium laurylsulfate (SDS) as well as the sorbitanfatty acid esters (Spane-types).

In addition and preferably also surfactants, emulsifiers and stabilizersare used, which are admitted for use in and on humans (e.g. auxiliaryagents having GRAS-status).

Especially for the W/O type dispersions, typical water-in-oilsurfactants are used for stabilization, sometimes in mixtures, also withO/W emulsifiers. Examples are the fatty alcohols,ethylenglycolmonostearate, glycerolmonostearate, sorbitan fatty acidesters (Span® series, e.g. the Span 20, Span 40, Span 60 and Span 80series, especially Span 85), ethers of fatty alcohols withpolyethylenglycol (PEG) (e.g. Brij® series), esters of fatty acids withPEG (e.g. Myrj® series).

Again, in general surfactants and stabilizers are preferred having anaccepted status, e.g. GRAS substances (Generally Regarded As Safe—FoodAdditives—GRAS substances, Food Drug Cosmetic Law Reports, Chicago(1994), Food Additive Database der FDA, Internet: www.fda.gov, 1999).

In case the dispersions according to the invention contain—additionallyto the oil droplets—particles of non-dissolved active ingredient, theparticle size should be as small as possible, e.g. to maintain physicalstability and avoiding sedimentation. In addition, in case ofintravenous administration the particles need to be small enough toavoid capillary blockade. The smallest capillaries being approximately5-6 μm in diameter. Therefore the particle diameter 90% should be below5 μm, preferentially also the diameter 95% and most preferentially thediameter 100% should be below 5 μm (measured by laser diffractometryafter separation of the particles from the dispersion by centrifugation,volume distribution data). It is even more beneficial that thesediameters are below 3 μm providing a certain safety distance to thesmallest capillaries. Most advantageous is a particle size ofnon-dissolved drug below 1000 nm (mean particle size measured by photoncorrelation spectroscopy). This size is far away from the 5-6 μmsmallest capillary diameter and simultaneously excludes anysedimentation effects (this size of particles does not sediment ratherindependent on the density of the drug). In case a more rapiddissolution of the drug crystals after administration of the dispersionis required, the mean PCS diameter should be in the range of 100 nm toapprox. 400 nm, most favorable below 100 nm.

Generally it is advantageous, to use the active ingredient in form ofvery fine crystals for the production of the dispersions, i.e. inmicronized form having a particle size in the range of about 0.1 μm-25μm (colloid mill, gas-jet mill). Preferred are average particle sizes of0.1 μm-5 μm, more preferred smaller than 1 μm.

The pH of the dispersions according to the invention is typicallybetween 4 and 8, preferably between 5 and 7.5, more preferred between 6and 7.5 and is determined in practice by way of the form or manner ofapplication.

The dispersion according to the invention may further contain aneffective amount of an antioxidant, such as vitamin E, in particular theisomer alpha-tocopherol. Alternatively, also beta- or gamma-tocopherol,or ascorbyl palmitate may be used. The amount added may be 10 mg to 2000mg, preferably 25 mg to 1000 mg, based on 100 g of triglyceride.

A typical dispersion according to the invention thus can comprise, basedon the ready-for-use-composition: 0.05 to 1.0 wt. %, preferably 0.05 to0.5 wt. % of active ingredient, 0.05 to 2 wt. % of emulsifier or amixture of emulsifiers, e.g. Tween 80 and/or egg-lecithin, dispersed ina O/W emulsion, which, based on the emulsion, contains 5 to 30 wt. %,preferably 10 to 20 wt. % triglycerides. The triglycerides arepreferably soya bean oil, medium-chain triglycerides (at least 90%C8/C10) as well as mixtures of soya bean oil and medium-chaintriglycerides (at least 90% C8/C10) in a weight ratio of 1:2 to 2:1,preferably 1:1. In addition also 0.5 to 5 wt. %, preferably 1 to 3 wt. %of typically used isotonisation agent, such as glycerol, and 0.005 to0.05 wt. % antioxidants, such as alpha-tocopherol, may be present, basedon the total composition. A particularly preferred active ingredient isamphotericin B. Further, also preservation agent may be added. This isin particular useful for packaging of the dispersions inmultidispense-containers.

The dispersions contains the active ingredient dissolved in an amount,which is greater than that amount which is the result of themathematical addition of its maximal solubility in each of the waterphase and the oil phase of the emulsion, which “addition amount” isdetermined under standard conditions (20° C., standard pressure) bydissolving the maximal amount of active ingredient in the separate oiland aqueous phases (maintaining the other dissolution conditionsidentical) corresponding to the proportions in the dispersion(saturation concentrations).

Typical active ingredient concentrations in the dispersion are 0.01 wt.% to 30 wt. %, preferably 0.1 wt. % to 10 wt. %, particularly preferred1 wt. % to 5 wt. %, based on the total amount of the dispersion.

Drugs of special interest—apart from amphotericin B—are vancomycin andvecuronium. Furthermore poorly soluble drugs can be taken from thegroups of the prostaglandines, e.g. prostaglandine E₂, prostaglandineF_(2á) and prostaglandine E₁, proteinase inhibitors, e.g. indinavire,nelfinavire, ritonavire, saquinavir, cytotoxics, e.g. paclitaxel,doxorubicine, daunorubicine, epirubicine, idarubicine, zorubicine,mitoxantrone, amsacrine, vinblastine, vincristine, vindesine,dactiomycine, bleomycine, metallocenes, e.g. titanium metallocenedichloride, and lipid-drug conjugates, e.g. diminazene stearate anddiminazene oleate, and generally poorly insoluble anti-infectives suchas griseofulvine, ketoconazole, fluconazole, itraconazole, clindamycine,especially antiparasitic drugs, e.g chloroquine, mefloquine, primaquine,pentamidine, metronidazole, nimorazole, tinidazole, atovaquone,buparvaquone, nifurtimoxe and anti-inflammatory drugs, e.g.cyclosporine, methotrexate, azathioprine.

Dispersions with anti-inflammatory drugs can be applied topically,orally and parenterally. In case of topical administration to the skin,the drug can penetrate into the tissue underneath to treat inflammatoryprocesses. In case of topical application to mucosal surfaces such asthe eye, diseases like the dry eye syndrome can be treated which arecaused by an underlying inflammatory process. Topical administration tomucosal surfaces in the vagina is also favorable, e.g. especially foranti-infectives. The dispersions spread well over the membrane surfacegiving an equal distribution of the drug. Especially in case thedispersions contain oil droplets and additionally ultrafine drugcrystals, these ultrafine crystals can adhere to the vaginal membraneand slowly dissolve providing prolonged drug action (depot). Foradministration to the eye it is favorable to use dispersions which arepositively charged. The interaction of positively charged particles withnegatively charged cell membranes will prolong the retention time.

Oral administration of the invented dispersions is favorable to increasethe bioavailability of poorly soluble drugs being not sufficientlyorally available, examples are paclitaxel and amphotericin B. Instead ofapplying an aqueous dispersion, the dispersions can also be transferredto a dry form by spray-drying or lyophilisation.

Parenteral, especially intravenous administration of drug-loadeddispersions can reduce the side effects, e.g. for doxorubicine,daunorubicine and Amphotericin B. Intravenously administered dispersionscan be directed to desired target sites such as the brain and the bonemarrow by modification of the surface with apolipoproteins. This is ofspecial interest of drugs which have no or only limited accessibility tothe brain and the bone marrow. Classical examples are cytotoxics such asdoxorubicine. Targeting of cytotoxic dispersions to the brain will allowto treat brain tumors which by now could only be treated by irradiationor locally, e.g. by implanting therapeutic devices or drug-loadedimplants. Dispersions with anti-infectives possessing poorblood-brain-barrier permeability could be used to deliver theseanti-infectives across the blood-brain-barrier to treat parasitespersisting in the brain.

The organ distribution of intravenously injected carriers is affected bythe physico-chemical properties such as particle size, particle chargeand surface hydrophobicity. For example, negatively charged particlesare taken up much faster by the macrophages of the liver than unchargedparticles (Wilkens, D, J. and Myers, P. A., Studies on the relationshipbetween the electrophoretic properties of colloids and their bloodclearance and organ distribution in the rat. Brit. J. Exp. Path. 47,568-576, 1966). To modulate the in vivo organ distribution the charge ofthe invented dispersions can therefore be changed, again especiallypositively charged dispersions are favorable. At the injection site thepositively charged dispersions can stick to negatively charged cellsurfaces. After intravenous injection the negatively charged dispersionparticles will interact with negatively charged proteins, especiallywith albumin being the most dominant protein in the blood. Albumin isknown as dysopsonine, therefore adsorption onto the droplet surface andformation of an albumin adsorption layer can prolong the retention timeof the invented dispersions in the blood (i.e. reduced uptake by themacrophages of the liver).

Positively charged dispersions according to the invention can beproduced by using positively charged surfactants or using positivelycharged surfactants in mixture with uncharged stabilizers (e.g.poloxamers) and/or negatively charged surfactants (e.g. lecithin).Positively charged dispersions according to the invention possess apositive zeta potential. The zeta potential of the dispersion particlesis determined by electrophoretic measurement in distilled water(conductivity adjusted to 50 μS/cm by addition of sodium chloride) or bymeasuring the particles in their original dispersion medium (i.e. outerphase of the dispersion). Examples for positively charged surfactantsand stabilizers are stearylamine, cetylpyridiniumchloride (CPC),positively charged lipids, e.g. N-[1-(2,3-dioleyloxy)propyl]-N,N,N-tromethylammoniumchloride (DOTMA), didodecyldimethylammoniumbromide(DDAB),2,3-dioleyloxy-N-[2(spermidincaroxamid)ethyl]-N,N-dimethyl-1-propylammoniumtrifluoro-acetate(DOSPA), 3â-[N-(N′,N′-dimethylaminoethan)carbamoyl]-cholesterol(DC-Chol).

Preparation of positively charged dispersions can be performed by usingthe positively charged surfactant or the surfactant mixture in theproduction process (de novo production). Alternatively, the positivelycharged surfactant can be added to a prepared negatively chargeddispersion. It needs to be added in such a quantity that charge reversalfrom negative to positive occurs.

Details of the production process: The mixture of lipid, drug, water andsurfactant or other stabilizers needs to undergo a higher energeticdispersion process. In case when using blends of oils and solid fats, itmight be sensible to dissolve a solid fat in the oil at elevatedtemperature before preparing the mixture. Preferred method for producingthe invented dispersion is high pressure homogenization, e.g. usingpiston-gap homogenizers or jet stream homogenizers. In case water is theouter phase of the dispersion, high pressure homogenization is performedbetween 0° C. and 100° C. Most efficient dispersion in combination withfast dissolution of the poorly soluble drug is achieved whenhomogenizing well above room temperature, e. i. between 35° C. and 100°C. Optimum homogenization temperatures considering simultaneously thechemical stability of the drug were found to be between 45° C. and 65°C. In case of highly temperature sensitive drugs, homogenization shouldbe performed close to the freezing point of water (e.g. approx. 4° C.).

In case liquids other than water are forming the outer phase of thedispersion possessing a boiling point above water, homogenization canalso be performed at higher temperatures or below 0° C. (e.g. PEG 600).

In case of lipid blends, blending the oil bulk with the solid lipid bulkmight lead to a solid bulk blend—despite the particles in the produceddispersion being liquid (Thomson effect). In such a case homogenizationshould be performed at temperatures above the melting point of the bulkblend. The same is valid when using a solid lipid only to produce thedispersion according to the invention. The homogenization pressureapplied can range from 10 bar to 11,000 bar. In case dispersions areproduced at 11,000 bar, the dispersions are sterile because the highpressure disrupts bacteria and viruses. If sterility by homogenizationis not desired, preferred production pressures are between 200 bar andapprox. 4000 bar. High pressure production lines running in industrywork typically between 200 bar and 700 bar, production at thesepressures would not require to buy new machines. However, production atlower pressures requires a higher number of cycles. In case a highernumber of cycles should be avoided (e.g. due to chemical stabilityaspects of the drug), a higher pressure should be applied ranging from700 bar to 4000 bar. For 700-1500 bar homogenizers from APV Gaulin(Lübeck, Germany) can be used, 700-2000 bar can be run with machinesfrom Niro Soavi (Lübeck, Germany), special homogenizers from the companyStansted allow pressures up to 4000 bar (Stansted, UK).

To produce the dispersion all homogenization equipment can be usedproviding a sufficiently high power density, that means typically above10⁴ W/m³. In some homogenizing machines the power density (dissipatedenergy per dispersion volume unit) cannot be calculated because theexact size of the dispersion volume is not known (e.g. microfluidizer).In such cases the suitability of the machine for producing the inventeddispersion can only be determined by an empirical trial. Examples forhomogenizers of the piston-gap type are the machines by the companiesAPV Gaulin, Niro Soavi, Stansted and also the French Press, an examplefor a jet stream homogenizer is the microfluidizer (Microfluidics, Inc.,USA).

The invention is further illustrated by way of the following examples,however, without limiting it thereto.

EXAMPLES Example 1

8 mg Amphotericin B were triturated with 40 g Lipofundin N 20% (0.2 mgAmphotericin B/ml emulsion) and the dispersion obtained was stirred withan Ultra-Turrax stirrer for 5 minutes at 8000 rpm. The dispersion wasthen subjected to high pressure homogenization with a Micron LAB 40 at1,500 bar with 20 cycles. The particle size was determined using a laserdiffractometer (Coulter LS 230, Coulter Electronics, USA). The diameterof 50% (D50%) of the volume distribution amounted to 0.164 μm, D90%,0.340 μm, D95%, 0.387 μm, D99% 0.466 μm, and D100% 0.700 μm.

Example 2

An emulsion system with Amphotericin B was produced as in Example 1, thequantity of Amphotericin B incorporated however amounted to 40 mg (i.e.1 mg/ml emulsion). The following diameters were measured: D50%, 0.160μm, D90%, 0.362 μm, D95%, 0.406 μm, D99% 0.485 μm, and D100% 0.746 μm.

Example 3

An emulsion was produced analogous to that of Example 1, however thequantity Amphotericin B incorporated amounted to 80 mg (i.e. 2 mg/mlemulsion). The following diameters were measured: D50%, 0.194 μm, D90%,0.381 μm, D95%, 0.423 μm, D99% 0.494 μm, and D100% 0.721 μm.

Example 4

40 mg Amphotericin B powder were triturated with 40 g oil (mixture 50:50of LCT and MCT) and the suspension obtained was stirred with anUltra-Turrax for 5 minutes as in Example 1. The suspension was thensubjected to high pressure homogenization with a Micron LAB 40 highpressure homogenizer with 2 cycles at 150 bar, 2 cycles at 500 bar, andthen 20 cycles at 1,500 bar. 8 g of the oily suspension obtained werethen dispersed in 32 g water, which contained 1.2% lecithin. Dispersionwas carried out with an Ultra-Turrax for 5 minutes at 8000 rpm. Thedispersion obtained was then subjected to high pressure homogenizationwith the Micron LAB 40 at 500 bar with 10 cycles. The followingdiameters were measured: D50%, 0.869 μm, D90%, 2.151 μm, D95%, 2.697 μm,D99% 3.361 μm.

Example 5

An emulsion was produced, analogous to Example 4, however the productionof the emulsion with high pressure homogenization was not carried out atroom temperature, but in a temperature-controlled LAB 40 at 50° C. Thefollowing diameters were measured: D50%, 0.647 μm, D90%, 1.537 μm, D95%,1.768 μm, D99% 2.152 μm, and D100% 3.310 μm.

Example 6

An Amphotericin B emulsion was produced by high pressure homogenization,analogous to Example 1 (0.2 mg Amphotericin B/ml emulsion), the highpressure homogenization of the emulsion took place at room temperature.The drug was triturated with a 1.2% aqueous Tween 80 solution, thesuspension pre-homogenized and 80 mg of this suspension was mixed with40 g Lipofundin N 20%. The following diameters were measured: D50% 0.142μm, D90% 0.282 μm, D95% 0.331 μm, D99% 0.459 μm, and D100% 0.843 μm.

Example 7

An emulsion was produced, analogous to Example 6, however theAmphotericin B concentration amounted to 1 mg/ml emulsion. The followingdiameters were measured: D50% 0.245 μm, D90% 0.390 μm, D95% 0.426 μm,D99% 0.489 μm, and D100% 0.700 μm.

Example 8

An emulsion was produced, analogous to Example 6, however theAmphotericin B concentration amounted to 2 mg/ml emulsion. The followingdiameters were measured: D50% 0.237 μm, D90% 0.389 μm, D95% 0.426 μm,D99% 0.491 μm, and D100% 0.701 μm.

Example 9

An emulsion was produced, analogous to Example 6, however the highpressure homogenization of the emulsion took place at 60° C. Thefollowing diameters were measured: D50% 0.197 μm, D90% 0.388 μm, D95%0.436 μm, D99% 0.532 μm, and D100% 0.953 μm.

Example 10

An emulsion was produced, analogous to Example 7, however thehomogenization pressure amounted to 500 bar instead of 1500 bar. Thefollowing diameters were measured: D50% 0.263 μm, D90% 0.401 μm, D95%0.435 μm, D99% 0.493 μm, and D100% 0.657 μm.

Example 11

The particle size distribution of the Amphotericin B powder was analyzedwith laser diffractometry and light microscopy. FIG. 1 (top) shows theparticle size distribution curve of the Amphotericin B powder followingdispersion in water, determined by laser diffractometry and the particlesize distribution after incorporation into the emulsion system accordingto the invention from Example 2 (FIG. 1, bottom). In the emulsion systemno Amphotericin B crystals remain detectable, Amphotericin B has beenincorporated into the emulsion system.

Example 12

The Amphotericin B emulsion was examined in comparison with AmphotericinB crystals dispersed in water, using light microscopy. FIG. 2 shows thelight microscopic photograph of the Amphotericin B powder in thepolarized light, because of the anisotropy of the crystals they appearlight. FIG. 3 shows the light-microscopic photograph in the polarizedlight following incorporation of Amphotericin B into the emulsion system(Example 1), anisotropic structures are no longer detectable, the wholepicture is almost black. For the light microscopy, the emulsion systemwas applied to the slide undiluted.

Example 13

Buparvaquone was incorporated into an emulsion system analogously to theAmphotericin B as in Example 6. The following diameters were measured:D50% 0.399 μm, D90% 0.527 μm, D95% 0.564 μm, D99% 0.635 μm, and D100%0.843 μm.

Example 14

Atovaquone was incorporated, analogously to Example 1, instead ofAmphotericin B into an emulsion system. The following diameters weremeasured: D50% 0.297 μm, D90% 0.437 μm, D95% 0.475 μm, D99% 0.540 μm,and D100% 0.744 μm.

Example 15

An emulsion was produced analogously to Example 1, however the quantityof Amphotericin incorporated amounted to 5 mg/ml emulsion. Thesolubility in the dispersion for Amphotericin was exceeded, drugcrystals were present besides oil drops (heterogeneous dispersion).

Example 16

An Amphotericin B emulsion was produced by adding 40 mg Amphotericin Bto 40 mL of Lipofundin N 20% (i.e. Amphotericin B 1 mg/ml emulsion). Themixture was homogenized at 45° C., 1500 bar for 10 cycles. Sterilizationwas performed by autoclaving at 121° C. for 15 minutes according to theGerman pharmacopoeia The PCS diameter before autoclaving was 203 nm, thepolydispersity index 0.102, after autoclaving the diameter was 208 nm,the polydispersity index 0.137.

Example 17

100 mg Amphotericin B powder were dispersed in 900 mg sterile water,pre-homogenized and dispersed in 20 g of MCT oil using pistil and mortarunder the addition of 1.2% lecithin. The oil was dispersed in 80 g waterand this mixture homogenized in a microfluidizer type Microfluidix M110y(i.e. Amphotericin B 1 mg/ml emulsion). Homogenization was performed at1000 bar for 10 minutes. PCS diameter before autoclaving was 192 nm, thepolydispersity index 0.113, after sterilization the diameter was 196 nm,the polydispersity index 0.109.

Example 18

The Amphotericin B emulsion from example 17 was analyzed undiluted forlarger particles and potential Amphotericin B crystals by taking lightmicroscopy graphs of the undiluted emulsion. FIG. 1 shows only a fewlarger droplets, no Amphotericin B crystals were detectable.

Example 19

Emulsions were produced as described in example 16, however 15homogenization cycles were applied. Two dispersions were producedcontaining 1 mg/mL Amphotericin B and 5 mg/mL Amphotericin B. Theemulsions were analyzed by taking light microscopy graphs. Lightmicroscopy of the dispersion with 1 mg/ml shows an emulsion system withno detectable Amphotericin B particles (FIG. 5), in the dispersion with5 mg/mL Amphotericin B besides the emulsion droplets very tinyAmphotericin B crystals are detectable (FIG. 6).

Example 20

An Amphotericin B emulsion was produced as described in example 16,production temperature was 65° C., 20 cycles were applied. The mean PCSdiameter was 255 nm, the polydispersity index 0.098. Laserdiffractometer analysis was performed using a Coulter LS 230 (CoulterElectronics, USA). The diameter 50% was 0.247 μm, the diameter 90% 0.410μm, the diameter 99% 0.566 μm and the diameter 100% 0.938 μm.Amphotericin B content was 1 mg/ml, sterilization was performed byautoclaving at 121° C. for 15 minutes. Drug content was analyzed byHPLC, in two samples 93.8% and 91.0% were recovered, respectively.

Example 21

100 mg cyclosporine were mixed with 40 g of Lipofundin N 20%,homogenization was performed at temperature of 25° C. applying 20 cyclesat 1500 bar. The mean PCS diameter was 234 nm, the polydispersity index0.099. The laser diffractometer diameter 50% was 0.218 μm, the diameter90% 0.381 μm and the diameter 100% 0.721 μm. In light microscopy nocyclosporine particles were detectable (polarized light, dark field).The zeta potential of the emulsion was determined in distilled waterwith conductivity adjusted to 50 μS/cm by addition of sodium chloride.Field strength was 20 V/cm, conversion of electrophoretic mobility tothe zeta potential was performed using the Helmholtz-Smoluchowskiequation. The zeta potential was −51 mV.

Example 22

A cyclosporine emulsion was produced as described in example 21, but0.5% cetylpyridinium chloride (CPC) were added in the productionprocess. The emulsion was positively charged, the zeta potential was +32mV.

Example 23

A cyclosporine emulsion was produced as described in example 21 butunder addition of 1.0% stearylamine. The PCS diameter was 247 nm, thepolydispersity index 0.088. The laser diffractometer diameter 50% was0.229 μm, the diameter 90% 0.389 μm and the diameter 100% 0.721 μm. Thezeta potential was +24 mV.

Example 24

A cyclosporine emulsion was produced de novo. The composition was 0.1%cyclosporine, 0.5% poloxamer 188, 0.5% egg lecithin lipoid E80, 0.15%stearylamine, 10% miglyol 812 and 2.25% glycerol for isotonicity andwater up to 100%. The lecithin was dispersed in the oil phase, apre-emulsion was prepared with all the other ingredients by high speedstirring, cyclosporine powder was added in the last step. This mixturewas homogenized at 45° C. applying 20 cycles and 1500 bar. The PCSdiameter was 226 nm, the polydispersity index 0.111. The laserdiffractometer diameter 50% was 0.200 μm, the diameter 90% 0.406 μm andthe diameter 100% 1.154 μm The emulsion was positively charged, the zetapotential was +31 mV.

Example 25

An O/W dispersion was produced being composed of 10 g water phasecontaining 25 mg Amphotericin, 0.5 g Span 85, 0.25 g Tween 80 andMiglyol 812 added to 50 g. 1.0 ml of Amphotericin suspension (2.5%Amphotericin/ml) stabilized with 2.4% lecithin lipoid E 80 was mixedwith distilled water to yield 10 g, Tween 80 was added to the waterphase, Span 85 to the oil phase. The water was dispersed in the oil byhigh speed stirring. The obtained pre-emulsion was homogenized at 90° C.applying 1500 bar and 20 homogenization cycles. Size analysis wasperformed by laser diffractometry (Mastersizer E, Malvern Instruments,UK). The diameter 50% was 2.25 μm, the diameter 90% 4.21 μm.

While the claimed invention has been described in detail and withreference to specific embodiments thereof, it will be apparent to one ofordinary skill in the art that various changes and modifications can bemade to the claimed invention without departing from the spirit andscope thereof.

1. A supersaturated dispersion which comprises: an oily phase; anaqueous phase, in the form of an oil-in-water emulsion or a water-in-oilemulsion; and at least one active ingredient that is only slightly orwith difficulty soluble in the oily phase and the aqueous phase, whereinthe dispersion is free from toxicologically dangerous organic solventsand the dispersion is supersaturated containing the active ingredientdissolved in a quantity that is at least 5 times greater than thequantity which results additively from its maximum solubility in theoily and the aqueous phase of the emulsion, said dispersion obtained bycombining; the aqueous phase, the oily phase, which oily phase is not oronly partially miscible with the aqueous phase, the surfactant orstabilizer, and a solid phase, which comprises the one activeingredient, to form a pre-dispersion, wherein the active ingredient issuspended in at least a portion of the aqueous phase before contactingthe active ingredient with the oily phase, which pre-dispersion ofliquid and solid phases is subjected to a high-energy homogenizationprocess wherein no toxicologically dangerous solvents are used, andwherein at least one of the at least one active ingredient isincorporated as solid particles into the liquid phases of the dispersionwithout previously being dissolved, the at least one active ingredientis pulverized to form particles, the particles of active ingredient aretriturated or mixed with an oil-in-water emulsion or a water-in-oilemulsion to form the pre-dispersion, or the at least one activeingredient is pulverized to form particles, the particles of activeingredient are added to a surfactant solution, said surfactant solutionis homogenized and mixed with an oil-in-water emulsion or a water-in-oilemulsion to form the pre-dispersion.
 2. Dispersion according to claim 1,wherein the active ingredient, in addition to the dissolved state, ispartially present in highly dispersed solid crystalline form, resultingin a dispersion with a heterogeneously dispersed phase of oil drops andactive ingredient crystals.
 3. Dispersion according to claim 2, whereinat least 90% of the active ingredient crystals present are smaller than5 μm, volume distribution determined by laser diffractometry. 4.Dispersion according to claim 2, wherein at least 95% of the activeingredient crystals present are smaller than 5 μm, volume distributiondetermined by laser diffractometry.
 5. Dispersion according to claim 2,wherein about 100% of the active ingredient crystals present are smallerthan 5 μm, volume distribution determined by laser diffractometry. 6.Dispersion according to claim 2, wherein at least 90% of the activeingredient crystals present are smaller than 3 μm, volume distributiondetermined by laser diffractometry.
 7. Dispersion according to claim 2,wherein at least 95% of the active ingredient crystals present aresmaller than 3 μm, volume distribution determined by laserdiffractometry.
 8. Dispersion according to claim 2, wherein about 100%of the active ingredient crystals present are smaller than 3 μm, volumedistribution determined by laser diffractometry.
 9. Dispersion accordingto claim 2, wherein at least 90% of the active ingredient crystalspresent are smaller than 1 μm, volume distribution determined by laserdiffractometry.
 10. Dispersion according to claim 2, wherein at least95% of the active ingredient crystals present are smaller than 1 μm,volume distribution determined by laser diffractometry.
 11. Dispersionaccording to claim 2, wherein about 99% of the active ingredientcrystals present are smaller than 1 μm, volume distribution determinedby laser diffractometry.
 12. Dispersion according to claim 1, whereinthe dispersion comprises an oil-in-water emulsion and contains about 5to about 99.5 wt. % of aqueous phase, based on the total weight of thedispersion.
 13. Dispersion according to claim 1, wherein the dispersioncomprises an oil-in-water emulsion and contains about 10 to about 95 wt.% of aqueous phase, based on the total weight of the dispersion. 14.Dispersion according to claim 1, wherein the dispersion comprises anoil-in-water emulsion and contains about 60 to about 95 wt. % of aqueousphase, based on the total weight of the dispersion.
 15. Dispersionaccording to claim 1, wherein the dispersion comprises an oil-in-wateremulsion and contains about 70 to about 95 wt. % of aqueous phase, basedon the total weight of the dispersion.
 16. Dispersion according to claim1, wherein the dispersion contains at least one selected from the groupconsisting of emulsifiers and stabilizers.
 17. Dispersion according toclaim 16, wherein the dispersion contains less than 15 wt. % ofemulsifiers and/or stabilizers, based on the total weight of thedispersion.
 18. Dispersion according to claim 16, wherein the dispersioncontains less than 10 wt. % of emulsifiers and/or stabilizers, based onthe total weight of the dispersion.
 19. Dispersion according to claim16, wherein the dispersion contains less than 2 wt. % of emulsifiersand/or stabilizers, based on the total weight of the dispersion. 20.Dispersion according to claim 16, wherein the dispersion contains fromabout 0.6 to about 1.2 wt. % of emulsifiers and/or stabilizers, based onthe total weight of the dispersion.
 21. Dispersion according to claim 1,wherein the dispersion comprises at least one emulsifier selected fromthe group consisting of egg lecithin, soya lecithin, phospholipids ofegg or soya, sorbitan esters, sorbitane trioleate, polyethylene glycolsorbitan esters, polyoxyethylene sorbitane monooleate, sodiumglycocholate, sodium lauryl sulphate, and mixtures thereof. 22.Dispersion according to claim 1, wherein the dispersion comprises atleast one stabilizer selected from the group consisting of blockco-polymers, poloxamers, Poloxamer 188 and 407, poloxamines, Poloxamine908, polyvinyl pyrrolidone, polyvinyl alcohol, gelatine, polysaccharide,hyaluronic acid, chitosan, derivatives of chitosan, polyacryl acid,derivatives of polyacryl acid, polycarbophil, cellulose derivatives,methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose,sugar esters, saccharose monostearate, sodium citrate individually, andmixtures thereof.
 23. Dispersion according to claim 1, wherein thedispersion comprises an oil-in-water emulsion and the oil phase used forthe preparation of the dispersion comprises lipids which are solid atroom temperature.
 24. Dispersion according to claim 1, wherein thedispersion comprises an oil-in-water emulsion and the oil phase used forthe preparation of the dispersion comprises lipids which are liquid atroom temperature.
 25. Dispersion according to claim 1, wherein thedispersion comprises an oil-in-water emulsion and the oil phase used forthe preparation of the dispersion comprises a mixture of one or morelipids which are liquid at room temperature with one or more lipidswhich are solid at room temperature.
 26. Dispersion according to claim25, wherein the mixture of liquid lipid:solid lipid varies from about99:1 to about 1:99 parts by weight.
 27. Dispersion according to claim26, wherein proportion of liquid lipid in mixture of lipids is at least10 parts by weight.
 28. Dispersion according to claim 26, whereinproportion of liquid lipid in mixture of lipids is at least 30 parts byweight.
 29. Dispersion according to claim 26, wherein proportion ofliquid lipid in mixture of lipids is at least 50 parts by weight. 30.Dispersion according to claim 1, wherein the oil phase comprises atleast one individual lipid or mixtures thereof selected from the groupconsisting of natural and synthetic triglycerides, natural and syntheticmonoglycerides, natural and synthetic diglycerides, self-emulsifyingmodified lipids, natural and synthetic waxes, fatty alcohols, esters offatty alcohols, ethers of fatty alcohols, hard wax, Imwitor 900,glycerol trilaurate, glycerol myristate, glycerol palmitate glycerolstearate, glycerol behenat, waxes, cetyl palmitate, carnauba wax, whitewax, hydrocarbons, and hard paraffin.
 31. Dispersion according to claim1, wherein the an oil phase comprises at least one selected from thegroup consisting of soya oil, safflower oil, long-chain triglycerides,medium-chain triglycerides, miglyols, fish oils, oils with an increasedconstituent of unsaturated fatty acids, and acetylated partialglycerides.
 32. Dispersion according to claim 1, wherein the aqueousphase comprises water or mixtures of water with water-miscible organicliquids.
 33. Dispersion according to claim 1, wherein the aqueous phasecomprises water and at least one liquid polyethylene glycol. 34.Dispersion according to claim 1, wherein the aqueous phase contains atleast one additive selected from the group consisting of electrolytes,non-electrolytes, glycerol, glucose, mannitol, xylite, gel formingagents, cellulose, and cellulose derivatives.
 35. Dispersion accordingto claim 1, wherein the active ingredient is selected from the groupconsisting of medical drugs for treatment of human or animal bodies. 36.Dispersion according to claim 1, wherein the dispersion contains one ormore active ingredients selected from the group consisting ofanaesthetics, antibiotics, antimycotics, antiinfectives, corticoids,hormones, antiestrogens antiseptics, vasoactivating agents, glaucoagents, beta blocker, cholinergics, sympathomimetics, carboanhydraseinhibitors, mydriatics, virustatics, agents for tumor therapy,antiallergics, vitamins, antiinflammytory drugs, immuno-supressives,ciclosporine, and any combination thereof.
 37. Dispersion according toclaim 1, wherein the dispersion is positively charged.
 38. Dispersionaccording to claim 1, wherein the dispersion comprises at least onepositively charged stabilizer.
 39. Dispersion according to claim 1,wherein the dispersion comprises at least on positively chargedstabilizer selected from the group consisting of stearylamine,positively charged phospholipids, and positively charged lipids. 40.Dispersion according to claim 1, wherein the dispersion comprises anoil-in-water emulsion adapted for intravenous injection, and wherein thedispersion comprises at least on positively charged stabilizer. 41.Dispersion according to claim 40, wherein the dispersion furtherincludes at least one lecithines or nonionic stabilizers.
 42. Dispersionaccording to claim 40, wherein the dispersion further comprises at leastone poloxamer polymer.
 43. Dispersion according to claim 1, wherein theactive ingredient comprises ciclosporine.
 44. Dispersion according toclaim 1, wherein the active ingredient comprises at least one selectedfrom the group consisting of anti-mycotics, Amphotericin B,anti-infectives, Buparvaquone, Atovaquone, immuno-suppressives,Cyclosporin A, natural and synthetic derivatives of Cyclosporin A, tumortherapy drugs, Paclitaxel, and Taxotere.
 45. Dispersion according toclaim 1, wherein the active ingredient has a solubility of less than 1part per 100 parts in the aqueous phase.
 46. Dispersion according toclaim 1, wherein the active ingredient has a solubility of less than 1part per 1000 parts in the aqueous phase.
 47. Dispersion according toclaim 1, wherein the active ingredient has a solubility of less than 1part per 10,000 parts in the aqueous phase.
 48. Dispersion according toclaim 1, wherein the active ingredient has a solubility of less than 1part per 100 parts in the oily phase.
 49. Dispersion according to claim1, wherein the active ingredient has a solubility of less than 1 partper 1000 parts in the oily phase.
 50. Dispersion according to claim 1,wherein the active ingredient has a solubility of less than 1 part per10,000 parts in the oily phase.
 51. Dispersion according to claim 1,wherein the size of water phase and oily phase droplets is less thanabout 10 μm.
 52. Dispersion according to claim 1, wherein the size ofwater phase and oily phase droplets is less than about 5 μm. 53.Dispersion according to claim 1, wherein the size of water phase andoily phase droplets is less than about 1 μm.
 54. Dispersion according toclaim 1, wherein a pH of the dispersion is between 4 and
 8. 55.Dispersion according to claim 1, wherein a pH of the dispersion isbetween 5 and 7.5.
 56. Dispersion according to claim 1, wherein a pH ofthe dispersion is between 6 and 7.5.
 57. Dispersion according to claim1, wherein the active ingredient is present in an amount of from about0.01 to about 30 wt. %, based on the total weight of the dispersion. 58.Dispersion according to claim 1, wherein the active ingredient ispresent in an amount of from about 0.1 to about 10 wt. %, based on thetotal weight of the dispersion.
 59. Dispersion according to claim 1,wherein the active ingredient is present in an amount of from about 1 toabout 5 wt. %, based on the total weight of the dispersion.
 60. Amedicament comprising the dispersion according to claim
 1. 61. Amedicament for treatment of mycoses, inflammations, allergic diseases,tumor diseases, cardiovascular diseases, viral and other infections, orfor conducting anaesthetic treatment comprising a dispersion accordingto claim
 1. 62. A medicament which can be administered intravenously,intra- and subcutaneously, intramuscularly, intra-articularly orintraperitoneally comprising a dispersion according to claim
 1. 63. Amedicament which has a prolonged residence time in the blood, comparedto negatively charged dispersions, comprising a dispersion according toclaim
 1. 64. Supersaturated dispersions in form of an oil-in-wateremulsion comprising: an oil phase; a water phase; one or moresurfactants or stabilizers; and one or more drugs being only slightly orpoorly soluble in the water and in the oil, the dispersions aresupersaturated and contain an incorporated amount of the drug indispersion that is at least 5 times higher than the additive solubilitycalculated from the drug solubility in the oil and water phases of thedispersion, and the dispersions are organic solvent-free, saiddispersion obtained by combining; the aqueous phase, the oily phase,which oily phase is not or only partially miscible with the aqueousphase, the surfactant or stabilizer, and a solid phase, which comprisesthe one or more drugs, to form a pre-dispersion, wherein the activeingredient is suspended in at least a portion of the aqueous phasebefore contacting the active ingredient with the oily phase, whichpre-dispersion of liquid and solid phases is subjected to a high-energyhomogenization process wherein no toxicologically dangerous solvents areused, and wherein at least one of the one or more drugs is incorporatedas solid particles into the liquid phases of the dispersion withoutpreviously being dissolved, the one or more drugs is pulverized to formparticles, the particles of drug are triturated or mixed with anoil-in-water emulsion or a water-in-oil emulsion to form thepre-dispersion, or the one or more drugs is pulverized to formparticles, the particles of drug are added to a surfactant solution,said surfactant solution is homogenized and mixed with an oil-in-wateremulsion or a water-in-oil emulsion to form the pre-dispersion. 65.Dispersions according to claim 64, wherein the concentration ofsurfactant, stabilizer or mixtures of surfactants and stabilizers isbetween 0.1% and 20% by weight.
 66. Dispersion according to claim 1,wherein the active ingredient is dissolved in a quantity that is atleast 10 times greater than the quantity which results additively fromits maximum solubility in the oily and the aqueous phase of theemulsion.
 67. Dispersions according to claim 64, wherein the activeingredient is dissolved in a quantity that is at least 10 times greaterthan the quantity which results additively from its maximum solubilityin the oily and the aqueous phase of the emulsion.
 68. A method for theproduction of a dispersion comprising: an oily phase; an aqueous phase,in the form of an oil-in-water emulsion or a water-in-oil emulsion; andat least one active ingredient that is only slightly or with difficultysoluble in the oily phase and the aqueous phase, wherein the dispersionis free from toxicologically dangerous organic solvents and thedispersion is supersaturated containing the active ingredient dissolvedin a quantity that is at least 5 times greater than the quantity whichresults additively from its maximum solubility in the oily and theaqueous phase of the emulsion, the method comprising: suspending theactive ingredient in at least a portion of the aqueous phase to form asuspension and mixing the suspension with said oily phase to form amixture; subjecting the mixture of liquid and solid phases to ahigh-energy homogenization process with a homogenizer without usingtoxicologically dangerous organic solvents, wherein one of: (a)incorporating the active ingredient as a solid into the liquid phases ofthe dispersion without previously being dissolved, (b) pulverizing theactive ingredient, triturating or mixing the pulverized activeingredient with an oil-in-water emulsion or a water-in-oil emulsion toform a pre-dispersion, and subjecting the pre-dispersion to thehomogenization or high pressure homogenization process, or (c)pulverizing the active ingredient, dispersing the pulverized activeingredient in a surfactant solution, homogenizing the dispersion to forma homogenized dispersion, then mixing the homogenized dispersion with anoil-in-water emulsion or a water-in-oil emulsion to form apre-dispersion, and subjecting the pre-dispersion to the homogenizationor high pressure homogenization process.